N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer
Adeline Berger, … , Himisha Beltran, David S. Rickman
Adeline Berger, … , Himisha Beltran, David S. Rickman
Published July 1, 2019
Citation Information: J Clin Invest. 2019;129(9):3924-3940. https://doi.org/10.1172/JCI127961.
View: Text | PDF
Research Article Genetics Oncology

N-Myc–mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Abstract

Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc–induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc–induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

Authors

Adeline Berger, Nicholas J. Brady, Rohan Bareja, Brian Robinson, Vincenza Conteduca, Michael A. Augello, Loredana Puca, Adnan Ahmed, Etienne Dardenne, Xiaodong Lu, Inah Hwang, Alyssa M. Bagadion, Andrea Sboner, Olivier Elemento, Jihye Paik, Jindan Yu, Christopher E. Barbieri, Noah Dephoure, Himisha Beltran, David S. Rickman

×

Figure 2

AR signaling alters the N-Myc transcriptome in vivo.

Options: View larger image (or click on image) Download as PowerPoint
AR signaling alters the N-Myc transcriptome in vivo. (A) Photomicrograph...
(A) Photomicrographs of H&E staining, vimentin (VIM), NCAM1, AR, cytokeratin 8 (KRT8), and 5 (KRT5) immunohistochemistry, and MYCN RNA in situ hybridization (RNAish) on primary prostate tumor region enriched with sarcomatoid differentiation (left) or liver metastatic lesion (right) from Pb-Cre+/– Ptenfl/fl LSL-MYCN+/+ mice 6 months after castration. Scale bars: 50 μm. (B) Photomicrographs of H&E staining or immunohistochemical staining for epithelial markers (AR and KRT8), a mesenchymal marker (VIM), or neural/ganglionic marker (S100) on 4-μm serial sections from mouse C1 (Supplemental Figure 2). Dotted lines indicate conventional adenocarcinoma adjacent to neural/ganglionic cells. Arrows indicate VIM+S100+ tumor cells that have invaded local vasculature. Scale bars: 50 μm. (C) Top: N-Myc signatures defined from 22Rv1-N-Myc xenografts versus 22Rv1 control (CTL) xenografts (–1 < log2[fold change] < 1, adj. P value < 0.05, n = 3 biological replicates per condition). Bottom: GSEA analysis results comparing N-Myc castrated tumors versus the other 3 groups of tumors. FC, fold change.